Effervescent compositions containing N-acetylcysteine

ABSTRACT

Effervescent pharmaceutical compositions containing a high amount of N-acetylcysteine and a method of treating acetaminophen poisoning with effervescent pharmaceutical compositions containing a high amount of N-acetylcysteine are described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/264,444 filed Apr. 29, 2014 which in turn is a continuation of U.S.application Ser. No. 13/466,721 filed May 8, 2012, the contents of eachof which are incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to effervescent pharmaceuticalcompositions containing N-acetylcysteine, more particularly toeffervescent compositions containing a high amount of N-acetylcysteineuseful for the oral treatment of acetaminophen poisoning.

BACKGROUND OF THE INVENTION

N-acetylcysteine (NAC) is a well-known drug approved worldwide forseveral indications mainly as mucolytic agent but it is also one of thefew available treatments for acetaminophen poisoning.

Acetaminophen (paracetamol) is a commonly used analgesic and antipyreticdrug. Accidental or suicidal acetaminophen overdose can cause severeliver damage which result in several deaths each year in the U.S.A.

NAC is effective by intravenous or oral route for the treatment ofacetaminophen poisoning if administered within 8-10 hours ofacetaminophen overdose. The dose of NAC to be administered is very highaccording to the Prescott therapy protocol, as reported in the followingtable 1:

TABLE 1 NAC doses according to the Prescott therapy protocol Body NACNAC weight loading maintenance (kg) dose (g) dose (g) 100-109 15 7.590-99 14 7 80-89 13 6.5 70-79 11 5.5 60-69 10 5 50-59 8 4 40-49 7 3.530-39 6 3 20-29 4 2

The only available NAC dosage form for the treatment of acetaminophenpoisoning is Acetadote®, 30 ml vials containing 200 mg/ml NAC forintravenous administration.

The oral treatment of acetaminophen poisoning with NAC is equally oreven more effective than intravenous treatment when administered within8-10 hours of acetaminophen overdose (Michele Zell Kanter, AmericanJournal of Health—System Pharmacy, Oct. 1, 2006 vol. 63 no. 19,1821-1827), the contents of which are incorporated herein by referenceand would be more practical and safer. However, the very high dosagelimits the possibility to use commercially available NAC formulationsfor oral administration which usually have a maximum NAC content of 600mg.

Therefore, it would be desirable to have an oral formulation containinga high amount of NAC to be used for the treatment of acetaminophenpoisoning.

SUMMARY OF THE INVENTION

We have now found an effervescent composition containing a high amountof NAC which is very easy to administer as an aqueous solution and isparticularly useful for the oral treatment of acetaminophen poisoning.

In a first aspect, the present invention relates to an effervescentcomposition containing at least 50% w/w of NAC, at least 20% w/w of acarbonate or bicarbonate salt and a mixture of pharmaceuticallyacceptable excipients comprising a sweetener, a flavor, and a diluent.

In a further aspect, the present invention relates to a method oftreating acetaminophen poisoning. The method includes administering aneffective amount of an effervescent composition containing at least 50%w/w of NAC, at least 20% w/w of a carbonate or bicarbonate salt and amixture of pharmaceutically acceptable excipients comprising asweetener, a flavor, and a diluent to a patient in need of suchtreatment.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The present invention relates to an effervescent composition containinga high amount of NAC which is particularly useful for the oral treatmentof acetaminophen poisoning.

The effervescent composition and object of the present inventioncontains at least 50% w/w of NAC, at least 20% w/w of a carbonate orbicarbonate salt and a mixture of pharmaceutically acceptable excipientscomprising a sweetener, a flavor, and a diluent.

As used herein, a value % w/w means the weight percent of a component ofthe composition with respect to the total weight of said composition.

In a preferred embodiment, the amount of NAC in the effervescentcomposition ranges from 50% to 80% w/w, more preferably, it is from 50%to 60% w/w.

In a particularly preferred embodiment of the present invention, theamount of NAC is about 54-55% w/w.

Suitable carbonate or bicarbonate salts are pharmaceutically acceptablecarbonate or bicarbonate salts commonly used as CO₂ source ineffervescent compositions.

Specific examples include sodium bicarbonate, sodium carbonate,potassium bicarbonate, potassium carbonate, sodium sesquicarbonate(NaHCO₃+Na₂CO₃+2H₂O), sodium glycine carbonate and the like.

Sodium bicarbonate is particularly preferred.

The amount of carbonate or bicarbonate salt in the effervescentcompositions according to the present invention is at least 20% w/w,preferably from 20% to 45% w/w, and more preferably from 30% to 35% w/w.

The Applicant has found that the formulation of the present inventiondevelops effervescence in water without the need of an additionalorganic or inorganic acid, making it particularly advantageous incomparison with known effervescent NAC compositions which require thepresence of an effervescent couple.

In addition to the active ingredient and the carbonate or bicarbonatesalt, the effervescent composition of the present invention usuallycontains a mixture of excipients comprising a sweetener, a flavor, and adiluent.

The total amount of the additional excipients is usually from 3.5% to15% w/w.

Suitable sweeteners include sugars, such as mono- or di-saccharides, forexample glucose, saccharose, maltose, galactose, and artificialsweeteners, such as sodium saccharin, acesulfame potassium, cyclamates,sucralose. Artificial sweeteners are preferred, and among them sucraloseis particularly preferred.

The amount of sweetener ranges from 0.2% to 10% w/w, and preferably isfrom 0.5% to 1% w/w.

The amount of flavor ranges from 1% to 3% w/w, and preferably is about2% w/w.

Any pharmaceutically acceptable flavors can be used such as fruitflavor, peppermint flavor, etc. Fruit flavors are preferred, and lemonand orange flavors are particularly preferred.

Suitable diluents include polyols, such as for example mannitol,sorbitol, xylitol, as well as cellulose, starch and maltodextrin.

Maltodextrin is particularly preferred.

The amount of diluent usually ranges from 2% to 20% w/w.

The effervescent composition according to the present invention canoptionally contain further pharmaceutically acceptable excipients suchas chelating agents, for example EDTA, lubricants, for example sodiumbenzoate and magnesium stearate, colorants, etc.

When a lubricant is present in the formulation according to the presentinvention, the amount of lubricant usually ranges from 0.1% to 5% w/w.

Sodium benzoate is preferably used.

The effervescent NAC compositions of the invention are prepared byconventional granulation techniques, preferably by wet granulation forexample in a fluid bed granulator.

The effervescent granulate can be used as such as finished dosage form,for example filled in sachets or can be compressed into tablets.

In a preferred embodiment, the pharmaceutical NAC composition accordingto the invention is in the form of effervescent tablets.

The dose of NAC contained in the finished dosage unit can range from 0.5g to 2.5 g without changing the physical properties of the solidcomposition.

In particular, the effervescent formulations according to the presentinvention are readily soluble in a small amount of water, have a goodtaste and are of limited dimensions to be easily stored and transported.

The unit dose of NAC can be for example 0.5 g, 1.0 g, 1.5 g, 2.0 g and2.5 g. Unit doses of 0.5 g and 2.5 g are particularly preferred becausethey can be easy combined to reach any therapeutic dose required by thePrescott therapy protocol as reported in the following table 2.

TABLE 2 Number of Number of Volume of tablets of the tablets of thereconstituted Body invention invention solution to be weight NAC (2.5 g(0.5 g administered to (Kg) (g) NAC/tablet) NAC/tablet) patients Loadingdose 100-109 15 6 0 About 200 mL 90-99 14 5 3 (a glass of water) 80-8913 5 1 70-79 11 4 2 60-69 10 4 0 50-59 8 3 1 40-49 7 2 4 30-39 6 2 220-29 4 1 3 Maintenance dose 100-109 7.5 3 0 About 200 mL 90-99 7 2 4 (aglass of water) 80-89 6.5 2 3 70-79 5.5 2 1 60-69 5 2 0 50-59 4 1 340-49 3.5 1 2 30-39 3 1 1 20-29 2 0 4

The above table clearly shows some of the most significant advantages ofthe effervescent composition of the present invention in the treatmentof acetaminophen poisoning.

The high content of NAC of the compositions together with their veryhigh solubility results in the possibility to easy adjust theadministered dose according to the therapy protocol by calculating thenumber of tablets (as multiple of the 2.5 g dose and/or as multiple ofthe 0.5 g dose) and to dissolve it into a glass of water.

The resultant solution contains the therapeutic dose of NAC, has a goodtaste, is very easy to administer to the patient.

The possibility to administer the effervescent compositions of theinvention in a glass of water is a remarkable advantage over thecommercially available NAC formulations used for the treatment ofacetaminophen poisoning.

The required therapeutic dose is very easy to calculate in terms ofnumber of tablets or sachets to dissolve.

The glass of water containing a therapeutic dose of NAC has a good taste(good patient compliance also in case of children) and does not requiretrained nurses to be administered, as in the case of NAC vials.

The following examples better illustrate the present invention withoutlimiting it.

EXAMPLE 1

NAC (543 g), sodium bicarbonate (348 g), maltodextrin (79.8 g),sucralose (7 g), and EDTA sodium (0.2 g) were granulated together withwater in a fluid bed granulator.

The granulate was then dried until a residual moisture content of notmore than 0.5%, unloaded from the fluid bed and blended with sodiumbenzoate (3 g) and orange flavor (19 g).

The resultant mixture was compressed into flat round tablets, 25 mmdiameter, weighing 4.6 g and containing 2.5 g NAC or into flat roundtablets, 14 mm diameter, weighing 0.92 g and containing 0.5 g NAC.

EXAMPLE 2

NAC (543 g), sodium bicarbonate (348.2 g), maltodextrin (79.8 g), andsucralose (7 g) were granulated together with water in a fluid bedgranulator.

The granulate was then dried until a residual moisture content of notmore than 0.5%, unloaded from the fluid bed and blended with sodiumbenzoate (3 g) and orange flavor (19 g).

The resultant mixture was compressed into flat round tablets, 25 mmdiameter, weighing 4.6 g and containing 2.5 g NAC or into flat roundtablets, 14 mm diameter, weighing 0.92 g and containing 0.5 g NAC.

EXAMPLE 3

NAC (543 g), sodium bicarbonate (351 g), maltodextrin (79.8 g),sucralose (7 g), and EDTA sodium (0.2 g) were granulated together withwater in a fluid bed granulator.

The granulate was then dried until a residual moisture content of notmore than 0.5%, unloaded from the fluid bed and blended with orangeflavor (19 g).

The resultant mixture was compressed into flat round tablets, 25 mmdiameter, weighing 4.6 g and containing 2.5 g NAC or into flat roundtablets, 14 mm diameter, weighing 0.92 g and containing 0.5 g NAC.

EXAMPLE 4

NAC (543 g), sodium bicarbonate (351.2 g), maltodextrin (79.8 g), andsucralose (7 g), were granulated together with water in a fluid bedgranulator.

The granulate was then dried until a residual moisture content of notmore than 0.5%, unloaded from the fluid bed and blended with orangeflavor (19 g).

The resultant mixture was compressed into flat round tablets, 25 mmdiameter, weighing 4.6 g and containing 2.5 g NAC or into flat roundtablets, 14 mm diameter, weighing 0.92 g and containing 0.5 g NAC.

EXAMPLE 5

NAC (543 g), sodium bicarbonate (351 g), maltodextrin (79.8 g),sucralose (7 g), and EDTA sodium (0.2 g) were granulated together withwater in a fluid bed granulator.

The granulate was then dried until a residual moisture content of notmore than 0.5%, unloaded from the fluid bed and blended with orangeflavor (19 g).

The resultant mixture was filled into paper/aluminum sachets, 40×60 mm,weighing 4.6 g and containing 2.5 g NAC or weighing 0.92 g andcontaining 0.5 g NAC.

EXAMPLE 6

NAC (543 g), sodium bicarbonate (351.2 g), maltodextrin (79.8 g), andsucralose (7 g) were granulated together with water in a fluid bedgranulator.

The granulate was then dried until a residual moisture content of notmore than 0.5%, unloaded from the fluid bed and blended with orangeflavor (19 g).

The resultant mixture was filled into paper/aluminum sachets, 40×60 mm,weighing 4.6 g and containing 2.5 g NAC or weighing 0.92 g andcontaining 0.5 g NAC.

What is claimed is:
 1. An oral effervescent composition comprising atleast 50% w/w of N-acetylcysteine, at least 20% w/w of a carbonate orbicarbonate salt, without an additional organic or inorganic acid, andfrom 3.5% to 15% w/w of a mixture of pharmaceutically acceptableexcipients comprising a sweetener, a flavorant, and a diluent, whereinthe oral effervescent composition results in an unit dose ofN-acetylcysteine selected from the group consisting of 0.5 g, 1.0 g, 1.5g, 2.0 g and 2.5 g.
 2. The oral effervescent composition according toclaim 1 wherein the amount of N-acetylcysteine is from 50% to 80% w/w ofthe composition.
 3. The oral effervescent composition according to claim2 wherein the amount of N-acetylcysteine is from 50% to 60% w/w of thecomposition.
 4. The oral effervescent composition according to claim 3wherein the amount of N-acetylcysteine is from 54% to 55% w/w of thecomposition.
 5. The oral effervescent composition according to claim 1,wherein the amount of the sweetener is from 0.2% to 10% w/w of themixture of pharmaceutically acceptable excipients.
 6. The oraleffervescent composition according to claim 5, wherein the amount of thesweetener is from 0.5 to 1% w/w of the mixture of pharmaceuticallyacceptable excipients.
 7. The oral effervescent composition according toclaim 1, wherein the amount of the flavorant is from 1% to 3% w/w of themixture of pharmaceutically acceptable excipients.
 8. The oraleffervescent composition according to claim 7, wherein the amount of theflavorant is about 2% w/w of the mixture of pharmaceutically acceptableexcipients.
 9. The oral effervescent composition according to claim 1,wherein the amount of the diluent is from 2% to 20% w/w of the mixtureof pharmaceutically acceptable excipients.
 10. The oral effervescentcomposition according to claim 1, wherein the carbonate or bicarbonatesalt is selected from the group consisting of sodium bicarbonate, sodiumcarbonate, potassium bicarbonate, potassium carbonate, sodiumsesquicarbonate, and sodium glycine carbonate.
 11. The oral effervescentcomposition according to claim 1, wherein the amount of carbonate orbicarbonate salt is from 20% to 45% w/w of the composition.
 12. The oraleffervescent composition according to claim 11, wherein the amount ofcarbonate or bicarbonate salt is from 30% to 35% w/w of the composition.13. The oral effervescent composition according to claim 1, wherein thesweetener is selected from the group consisting of sugars and artificialsweeteners.
 14. The oral effervescent composition according to claim 13,wherein the artificial sweetener is selected from the group consistingof sodium saccharin, acesulfame potassium, cyclamates, and sucralose.15. The oral effervescent composition according to claim 14, wherein theartificial sweetener is sucralose.
 16. The oral effervescent compositionaccording to claim 1, wherein the diluent is selected from the groupconsisting of polyols, cellulose, starch and maltodextrin.
 17. The oraleffervescent composition according to claim 16, wherein the diluent ismaltodextrin.
 18. The oral effervescent composition according to claim1, further comprising a lubricant.
 19. The oral effervescent compositionaccording to claim 18, wherein the lubricant is sodium benzoate.
 20. Theoral effervescent composition according to claim 1 obtained by wetgranulation in a fluid bed granulator.